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Aims: Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that, in some instances, may show a granulomatous reaction associated with a favourable prognosis and occasional spontaneous regression. In the present study, we aimed to define the tumour microenvironment (TME) in four such cases, two of which regressed spontaneously., Methods and Results: All cases showed aggregates of tumour cells with the typical morphology, molecular cytogenetics and immunophenotype of BL surrounded by a florid epithelioid granulomatous reaction. All four cases were Epstein-Barr virus (EBV)-positive with type I latency. Investigation of the TME showed similar features in all four cases. The analysis revealed a proinflammatory response triggered by Th1 lymphocytes and M1 polarised macrophages encircling the neoplastic cells with a peculiar topographic distribution., Conclusions: Our data provide an in-vivo picture of the role that specific immune cell subsets might play during the early phase of BL, which may be capable of maintaining the tumour in a self-limited state or inducing its regression. These novel results may provide insights into new potential therapeutic avenues in EBV-positive BL patients in the era of cellular immunotherapy., (© 2021 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Aims: Mantle cell lymphoma (MCL) is characterized by distinctive histological and molecular features. Aberrant expression of BCL6 and CD10 has been reported occasionally, but the biological features of such cases are largely unknown. This study aimed to define the epidemiological, histological and cytogenetic characteristics of BCL6 and CD10-positive MCLs, also investigating possible biological features., Methods and Results: A total of 165 cases of cyclin D1 and t(11;14)(q13;q34)-positive MCLs were studied for CD10 and BCL6 immunohistochemical expression, which was documented in 26 of 165 (15.8%) cases (BCL6 17 of 165; CD10 11 of 165; BCL6 and CD10 co-expression two of 165). CD10-positivity was significantly more frequent in females (63.3%; P < 0.01). Either expression correlated significantly with higher mean proliferation index and higher prevalence of MUM1 positivity (P < 0.05). Fluorescence in-situ hybridization (FISH) for BCL6 (3q27) gene derangements was performed on the BCL6- and CD10-positive cases and 98 matched controls: amplifications were documented more frequently in BCL6-positive than -negative cases (50.0% versus 19.4% of cases) (P < 0.05). The mutational status of the variable immunoglobulin heavy chain genes (IGVH) was investigated by Sanger sequencing: five of the six successfully tested cases (83.3%) showed no somatic hypermutations., Conclusions: Aberrant CD10 and BCL6 expression defines a subset of MCLs with higher mean Ki-67 index and higher prevalence of MUM1 expression. BCL6 protein positivity correlates with cytogenetic aberrations involving the BCL6 gene. Although examined successfully in few cases, the high prevalence of unmutated IGVH genes also points at a pregerminal cell origin for these phenotypically aberrant cases., (© 2017 John Wiley & Sons Ltd.)

Aims: Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase involved in glycogen metabolism, cell cycle progression, differentiation, embryogenesis, migration, metabolism, survival and cellular senescence. Its main biological function is to inhibit β-catenin by sequestration and promotion of its proteasomal degradation in the Wnt canonical pathway; however, GSK-3β interacts with multiple signalling pathways, and aberrant expression of the enzyme was reported in many solid neoplasms. This study aimed to investigate the biological relevance of GSK-3β in classical Hodgkin lymphomas (cHL)., Methods and Results: We analysed the functional status of GSK-3β enzyme in cHL by using antibodies raised against fixation-resistant epitopes of phospho Y216 GSK-3β (active form), phospho S9 GSK-3β (inactive form) and β-catenin protein. We first detected the pY216 GSK-3β active form of the enzyme in 100 of 100 (100%) of the cases, and in line with the latter expression profile, the β-catenin protein was found in only 12 of 100 (12%) of the samples. As reported previously in bladder cancer, pancreatic adenocarcinoma and chronic lymphocytic leukaemia, we showed an aberrant nuclear localization in the neoplastic clone of active pY216 GSK-3β in 78 of 100 (78%) of cHL cases., Conclusions: We demonstrated the activation of GSK-3β in cHL resulting in inhibition of the Wnt/β-catenin signal cascade and the aberrant accumulation of its activated form in nuclei of Hodgkin Reed-Sternberg and Hodgkin cells. These findings may be relevant for future clinical studies, identifying GSK-3β as a potential therapeutic target for cHL., (© 2017 John Wiley & Sons Ltd.)

Aims: High levels of vascular endothelial growth factor A (VEGFA) seem to herald a worse prognosis in mycosis fungoides (MF). In this study, we aimed to characterize more clearly VEGFA gene and protein expression in MF., Methods and Results: First, we compared VEGFA mRNA levels in MF and in normal T lymphocyte samples; significantly higher VEGFA levels were found in MF. We then studied VEGFA expression in different normal T cell subsets, focusing on CD4(+) , CD8(+) , resting and activated T lymphocytes. We applied the gene signatures of the normal T cell subsets to MF samples and found that activated T lymphocytes represented the closest normal counterpart of the tumour. However, VEGFA mRNA levels were significantly higher in MF than in activated normal T cells, suggesting that VEGFA overexpression in MF represents an attribute acquired during neoplastic transformation: no significant VEGFA expression differences were recorded between early and advanced stages. Gene expression profile results were supported by immunohistochemistry in routine sections from 27 MF cases., Conclusions: For the first time, we demonstrate VEGFA expression in MF cells, suggesting that the VEGF pathway may be implicated in MF pathogenesis and can represent a novel therapeutic target., (© 2014 John Wiley & Sons Ltd.)

Aims: We describe a new rabbit monoclonal antibody, raised against a fixation-resistant epitope of the transcription regulator LIM domain only 2 (LMO2)., Methods and Results: Lymphoma cell lines and a large series of normal and neoplastic samples were investigated by Western blot and immunohistochemistry. The antibody detected nuclear positivity for the protein, with the exception of a proportion of classical Hodgkin lymphomas (HLs), peripheral T cell lymphomas (PTCLs) and solid tumours that showed granular cytoplasmic staining. In normal lympho-haematopoietic tissues, LMO2 was expressed at different intensities by CD34(+) blasts, haematopoietic precursors, germinal centre (GC), mantle and splenic marginal zone B cells. While reactive with only scattered elements in the thymus and nine of 237 PTCLs, the antibody stained 31 of 39 T-acute lymphoblastic lymphoma/leukaemias (T-ALLs) and the T-ALL-derived human leukaemic cell line, CCRF-CEM. LMO2 was found in 88% of B-acute lymphoblastic lymphoma/leukaemias (B-ALLs), 5% chronic lymphocytic leukaemias (CLLs) and 14%, 57% and 41% of mantle, follicular and Burkitt lymphomas, respectively. In the setting of diffuse large B cell lymphomas (DLBCLs), LMO2-positivity was related strongly to a GC phenotype. LMO2 was found in 83% primary mediastinal large B cell lymphomas (PMBLs) and 100% nodular lymphocyte predominant Hodgkin lymphomas (NLPHLs), whereas only 10% of classical HLs were stained. Acute and chronic myeloid leukaemias were usually positive., Conclusions: The new anti-LMO2 antibody can be applied confidently to routine sections, contributing to the differential diagnosis of several lymphoma subtypes, subtyping of DLBCLs and potential development of innovative therapies., (© 2012 Blackwell Publishing Ltd.)

Two monoclonal antibodies, MRK16 and C219, both directed at the 170 kDa P-glycoprotein multidrug resistance agent, were applied to frozen sections or cytospin preparations from normal human tissues and 60 non-Hodgkin's malignant lymphomas. Adrenal gland, kidney, liver and pancreas were always stained by the reagents, albeit with slightly different patterns. Brain capillaries as well as macrophages and some elements of the bone marrow, peripheral blood, ovarian stroma and colonic, gastric and jejunal mucosa were positive in all examined preparations. There were differences in the staining patterns with the two antibodies. Among the 60 non-Hodgkin's lymphomas, 25 contained a number of positive cells, which ranged from 2% to 100%. No correlation was seen between the expression of P170 and histological type, stage, clinical symptoms or growth fraction. A close relationship was shown between the presence of P170 positive elements and the clinical course of the disease (P less than 0.001).